It is now becoming clear that the podocyte plays a key role in progressive glomerulosclerosis associated with diabetes, hypertension and other forms of glomerular diseases that make up 90% of causes of progressive renal failure and that costs in excess of $12 billion per year in the US alone. Understanding the cell biology and pathology of the podocyte is therefore central to learning how to prevent progression of renal failure in man. This application will focus on podocyte biology. It will build on the critical mass of investigators at the University of Michigan who have developed new approaches and technologies in podocyte research as well as bring new investigators into this field. The application has four major projects. A mouse Transgenic Development Core (Larry Holzman) will develop transgenic model systems where proteins can be turned on and off specifically in podocytes at predetermined times to evaluate their contribution to podocyte structure and function. This will be a powerful tool for the renal community as a whole. Project 1 (Ben Margolis) will build on spectacular new progress in understanding how protein:protein interaction guides cellular mechanisms regulating podocyte structure and function. Project 2 (Friedhetm Hildebrandt) will use genetic approaches to identify a gene(s) responsible for the major cause of nephrotic syndrome in children (Steroid responsive NS) in man. Project 3 (Roger Wiggins) will use transgenic approaches to test the key hypothesis that loss of podocytes from the glomerulus is a major mechanism underlying glomerulosclerosis. These projects will be supported by a Morphology Core (Paul Killen) that includes a major international podocyte investigator (Dontcho Kerjaschki, University of Vienna) who will partner with us. An Administrative Core will coordinate the projects. Two Pilot and Feasibility projects (Kunliang Guan and David Kurnit) have been selected to be supported by the Center. They will focus on a Polycystin-1 -interacting protein (TSC-2) and development of a method for monitoring podocyte loss into the urine respectively. This application builds on the conclusion that the time is now right for a sustained and coordinated effort to investigate podocyte biology at the University of Michigan and world-wide.